Myocardial hypertrophy and its transition to failure remains a significant cause of morbidity and mortality. Sustained production of inflammatory cytokines is a hallmark of all phases of this transition. In particular, interleukin (IL)-18 is upregulated in heart failure, which directly correlates with the severity of myocardial damage and dysfunction, and poor clinical outcome in heart failure. Our preliminary studies demonstrate that IL-18 induces cardiomyocyte hypertrophy and fibroblast migration and proliferation in vitro, suggesting potential pro-hypertrophic and pro-fibrotic roles for IL-18 in vivo. Our studies in wild-type mice show that pressure overload induced by transverse aortic constriction (TAC) leads to left ventricular hypertrophy (LVH) and increased IL-18 expression. Remarkably, this hypertrophy can be significantly reduced by IL-18 neutralizing antibodies. IL-18 knockout mice develop significantly less LVH in response to TAC;conversely, cardiac-specific overexpression of IL-18 induces LVH and heart failure in the absence of TAC. Rabbit models also exhibit LVH and increased IL-18 expression in response to TAC. Furthermore, our preliminary human studies clearly demonstrate the prognostic power of systemic IL-18 levels to predict cardiac failure. Thus, our central HYPOTHESIS is that IL-18 is a key mediator of LVH and failure that results in pathological remodeling through the induction of hypertrophy-associated kinases, fetal genes, growth factors, and matrix metalloproteinases. To address this HYPOTHESIS, we will investigate IL-18-dependent signaling in cardiomyocytes in vitro (Specific Aim 1), the molecular mechanisms involved in IL-18-mediated cardiac fibroblast migration and proliferation in vitro (Specific Aim 2), and the causal role of IL-18 in LVH, fibrosis and failure in vivo, using cardiac-restricted IL-18KO and cardiac-specific IL-18 transgenic mice (Specific Aim 3). Results obtained in mice will be validated in a rabbit model of pressure-overload hypertrophy and failure. Systemic IL-18 levels will be measured and correlated with the relative severity of cardiac hypertrophy and failure in humans. Collectively, these proposed studies will establish IL-18 as a potentially use therapeutic target to attenuate the progression of LVH to cardiac failure.
t Narrative Myocardial hypertrophy and its transition to congestive heart failure are important diseases, resulting in quarter million deaths and one million hospitalizations annually in the US. Understanding the molecular mechanisms underlying these pathological processes will help us design more effective therapeutic strategies to better care for these patients. The primary goal of this proposal is to better understand the role of inflammatory cytokines, interleukin-18 in particular, in myocardial hypertrophy and its transition to failure.
|Yoshida, Tadashi; Friehs, Ingeborg; Mummidi, Srinivas et al. (2014) Pressure overload induces IL-18 and IL-18R expression, but markedly suppresses IL-18BP expression in a rabbit model. IL-18 potentiates TNF-?-induced cardiomyocyte death. J Mol Cell Cardiol 75:141-51|
|Siddesha, Jalahalli M; Valente, Anthony J; Yoshida, Tadashi et al. (2014) Docosahexaenoic acid reverses angiotensin II-induced RECK suppression and cardiac fibroblast migration. Cell Signal 26:933-41|
|Valente, Anthony J; Irimpen, Anand M; Siebenlist, Ulrich et al. (2014) OxLDL induces endothelial dysfunction and death via TRAF3IP2: inhibition by HDL3 and AMPK activators. Free Radic Biol Med 70:117-28|
|Siddesha, Jalahalli M; Valente, Anthony J; Sakamuri, Siva S V P et al. (2014) Acetylsalicylic acid inhibits IL-18-induced cardiac fibroblast migration through the induction of RECK. J Cell Physiol 229:845-55|
|Venkatesan, Balachandar; Valente, Anthony J; Das, Nitin A et al. (2013) CIKS (Act1 or TRAF3IP2) mediates high glucose-induced endothelial dysfunction. Cell Signal 25:359-71|
|Valente, Anthony J; Yoshida, Tadashi; Izadpanah, Reza et al. (2013) Interleukin-18 enhances IL-18R/Nox1 binding, and mediates TRAF3IP2-dependent smooth muscle cell migration. Inhibition by simvastatin. Cell Signal 25:1447-56|
|Valente, Anthony J; Sakamuri, Siva S V P; Siddesha, Jalahalli M et al. (2013) TRAF3IP2 mediates interleukin-18-induced cardiac fibroblast migration and differentiation. Cell Signal 25:2176-84|
|Valente, Anthony J; Yoshida, Tadashi; Clark, Robert A et al. (2013) Advanced oxidation protein products induce cardiomyocyte death via Nox2/Rac1/superoxide-dependent TRAF3IP2/JNK signaling. Free Radic Biol Med 60:125-35|
|Siddesha, Jalahalli M; Valente, Anthony J; Sakamuri, Siva S V P et al. (2013) Angiotensin II stimulates cardiac fibroblast migration via the differential regulation of matrixins and RECK. J Mol Cell Cardiol 65:9-18|
|Yeh, C-K; Chandrasekar, B; Lin, A L et al. (2012) Cellular signals underlying ?-adrenergic receptor mediated salivary gland enlargement. Differentiation 83:68-76|
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